Technical Field
The invention relates to an implantable assembly for locationally selective acquisition of neuronal electrical signals which propagate along at least one nerve fiber contained in a nerve fiber bundle, as well as to selective electrical stimulation of the at least one nerve fiber. The implantable assembly comprises an implantable electrode assembly which can be positioned around a nerve fiber bundle in a cuff, by which electrical signals can be applied to selected nerve fibers within the nerve fiber bundle. The electrical stimulation is in particular carried out by specifically manipulating the blood pressure in an animal or human patient.
Description of the Prior Art
Arterial hypertension is a global and typical disease of civilization which threatens the lives of millions of patients and at the same time places a huge burden on the health services. Therapeutic measures until now have been based on the administration of blood pressure-reducing medication such as ACE inhibitors, beta blockers, etc., but in addition to the desired blood pressure-reducing effect, they are associated with substantial side effects such as, for example, bradycardia, heart failure, asthma attacks, etc. In addition, despite the development of new blood pressure-reducing drugs, in up to 30% of all patients taking similar medication, a sufficient target blood pressure cannot be obtained. See the paper by H R Black et al., “Principal Results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (Convince)”, TRIAL, Jama, 289 (16), pp 2073-2082, 2003.
A further therapeutic approach to combatting high blood pressure follows on from a study by the Applicant which has been published in the article by Dennis T T Plachta, Oscar Cota, Thomas Stieglitz, Mortimer Gierthmuehlen, “Selektive Ableitung and Stimulation für ein blutdrucksenkendes Implantat unter Verwendung von Vielkanal-Cuff-Elektroden” [Selective Recording and Stimulation for a Blood Pressure-Reducing Implant Using Multi-Channel Cuff Electrodes], tm-Technisches Messen, 2013, vol 80 (5), pp 163-172. The results obtained by animal tests carried out on rats give rise to the possibility of detecting neuronal electrical signals in a locationally resolved manner from the nerve fiber bundle section by an electrode assembly implanted on a nerve fiber bundle section of the vagus nerve, as well as applying electrical signals to selected nerve fibers to stimulate them for the purposes of a technologically initiated blood pressure reduction. Stimulation of the vagus nerve of this type thus in principle has the potential of becoming an alternative treatment for therapy-refractory blood pressure.
The concept of selective vagus nerve stimulation is based on many years' experience in applying and establishing neuromodulatory therapy of severe forms of epilepsy, in which the vagus nerve is electrically stimulated in its entirety with the aid of an implanted electrode assembly in order to mitigate at least their extent as regarding severity and duration of incipient epileptic episodes. In this regard see F Sidiqui et al. “Cumulative Effect of Yagus Nerve Stimulators on Intractable Seizures Observed Over a Period of 3 Years”, Epilepsy and Behavior, 18 (3), pp 299-302, 2010, as well as T Stieglitz, “Neuroprothetik und Neuromodulation—Forschungsansatze und klinische Praxis bei Therapie und Rehabilitation” [Neuroprosthetics and neuromodulation—research strategies and clinical practice in therapy and rehabilitation], Bundesgesundheitsblatt—Gesundheitsforschung—Gesundheitsschutz, 53 (8), pp 783-790, 2010.
In contrast, for the chronic treatment of hypertension, the fibers relevant to blood pressure initially have to be located metrologically in order to then selectively electrically stimulate them in a particular manner. In order to protect the vagus nerve as far as possible from the positioning of an electrode assembly by implantation and in order to irritate the epineurium of the vagus nerve as little as possible, in the cited contribution by Dennis T T Plachta et al., the use of what is known as a cuff electrode is proposed which can be extraneurally attached to the vagus nerve. This has the advantage that the cuff electrode is relatively easy to position along the vagus nerve and, moreover, means that surgical intervention is only slightly invasive for a patient and thus goes easy on the patient and is also rapid to carry out.
The baroreflex acts to regulate blood pressure naturally; it constitutes a homeostatic, self-regulating mechanism and reflexively activates various effectors in the event of an elevated blood pressure. The heart rate is reduced, inter alia, as well as dilating the arterial vessels in order to reduce the blood pressure. In the case of a low blood pressure, the baroreflex is suppressed, whereupon the heart rate rises and blood vessels are constricted so that the blood pressure rises once again. The sensory inputs for the baroreflex are known as baroreceptors which, inter alia, are located in the walls of the aortic arch. From here, the blood pressure information runs monosynaptically along the nerve fibers relevant to blood pressure, hereinafter termed baroreceptive fibers, to the brain stem. When a threshold for the blood pressure is exceeded, the baroreflex triggers inhibition of sympathetic nerve fibers, leading to an immediate drop in the blood pressure. With the aid of the cuff electrode shown here in FIGS. 2a and 2b, it is possible to exploit this baroreflex mechanism by selectively detecting the pressure information supplied to the brain stem and simultaneously selectively “overwriting” it in order in this manner to suggest a substantially increased blood pressure situation to the brain stem, whereupon a natural significant drop in blood pressure is initiated.
FIG. 2a shows the known cuff electrode E in a planar view, in a planar unfolded state. FIG. 2b shows the cuff electrode E when implanted, in which regions B1 and B2 of the cuff electrode E have been folded on top of each other in order to save space and, moreover, a support substrate region 1B of the cuff electrode E provided with a first electrode assembly 2 surrounds a region of the nerve fiber bundle NFB in a cuff.
The cuff electrode E consists of a flexible, biocompatible support substrate 1 which in the embodiment shown is a polyimide film approximately 11 μm thick on which is positioned, on the top of the support substrate facing the plane of the drawing in FIG. 2a, a first electrode assembly 2 composed of a plurality of individual electrodes for the purposes of spatially resolved acquisition of neuronal electrical signals as well as for selective electrical stimulation of individual nerve fibers NF running in the nerve fiber bundle NFB. The individual electrodes of the first electrode assembly 2 come into direct superficial contact with the epineurium EPI of the nerve fiber bundle NFB because, by appropriate application of mechanical pretensioning, the support substrate 1 in the support substrate region 1B has rolled itself up, forming a support substrate surface 1′ in the form of a right cylinder facing the nerve fiber bundle NFB, as can be seen in FIG. 2b. In this manner, the individual electrodes of the first electrode assembly 2 assume an annular shape in space in the circumferential direction U curved around the nerve fiber bundle NFB.
Both for locationally selective acquisition of neuronal electrical signals and also for selective electrical stimulation of at least one nerve fiber NF, three first electrode structures 3 are provided which are each disposed at equal axial distances from each other which comprise, in the circumferential direction U, at least two electrode contacts 4, or eight as illustrated in the embodiment of FIG. 2a, b. The respective eight first electrode contacts 4 belonging to a first electrode structure 3 are disposed evenly in the circumferential direction U, that is at 45° with respect to each other. This enables eight-fold locational selectivity in the circumferential direction for locationally selective acquisition of neuronal electrical signals from the nerve fiber bundle NFB to be investigated. The first electrode strips 5 disposed respectively axially on both sides next to the three first electrode structures 3, which completely surround the nerve fiber bundle NFB, act as a ground potential in the event of locationally selective acquisition of neuronal electrical signals. However, if selectively targeted nerve fibers NF within the nerve fiber bundle NFB are to be stimulated electrically, then these first electrode strips 5 each act as an anode or as a counter-pole.
The threefold or tripolar disposition of the respective first electrode structures 3, by means of which respective first electrode contacts 4 acquire monopolar neuronal electrical signals, or electrical signals can be emitted for the purposes of locationally selective stimulation, allows impedance changes due to tissue growth at the metallic electrode contacts 4 to be determined and to be eliminated by the processing technology; on the other hand, neuronal signals relevant to blood pressure which run through the tripole assembly axially along an appropriate nerve fiber NF with a slight time delay, can be detected by means of appropriate tripolar amplification. In addition to the first electrode structures 3 described above as well as first electrode strips 5 which each assume a circular shape, which are all are positioned on the support substrate surface 1′ facing the plane of the drawing in FIG. 2a and which end proximally in connection structures V via corresponding electrical lines L, a second electrode assembly in the form of reference electrodes 12 is positioned on the rear of the support substrate 1 which on the one hand serves to acquire the intracorporeal electrical background ground signal or noise level which is at the basis of the signal analysis, on the other hand allows ECG signals to be acquired with the aid of the cuff electrode E. The electrode assembly which can be implanted as a cuff electrode can be connected, via the electrical connection structures V, with a hermetically encapsulated signal detector and generator 6 which is also configured as an implant.
With the known implantable electrode assembly, in the context of animal experiments on rats, it has been shown that with the aid of the total of 24 first electrode contacts distributed evenly around the nerve fiber bundle NFB as tripoles, blood pressure-correlated neuronal electrical time signals, hereinafter termed baroreceptive signals, can be acquired which furthermore, because their signal level is a function of circumferential direction, can act to localize the baroreceptive nerve fibers. Stimulation is tripolar, with that electrode contact 4 or those electrode contacts 4 of the centrally disposed first electrode structure 3 of the tripole assembly being used to detect the respective largest signal level of the baroreceptive signals. It has been shown that, by means of selective stimulation of baroreceptive nerve fibers, the blood pressure can be reduced reliably and significantly, wherein only very slight bradycardia (pulse reduction below 60 beats per minute) as well as barely noticeable bradypnoea (slowing of breathing to less than 20 breaths per minute) occurred.
In order to selectively electrically stimulate the baroreceptive nerve fibers, electrical stimulation signals were applied, on the basis of a specific combination of fixed predetermined stimulation parameters, to the respective selected electrode contacts 4 of the centrally disposed electrode structure. In this regard, the stimulation signals in the form of electrical stimulation events were applied to the selected nerve fibers at freely selectable intervals; as an example, every 20 seconds an electrical stimulus composed of 100 individual pulses was applied to the nerve fiber bundle via the respective selected electrode contact(s). Each individual pulse in this respect had a stimulation pulse duration of 0.6 ms with an anodic or cathodic stimulation amplitude of 0.8 mA respectively, whereupon electrode polarization was made possible. With a repetition rate for the individual pulse, what is known as the stimulation frequency, of 40 Hz, the total duration of an individual electrical stimulus was 100×25 ms, i.e. 2.5 seconds. In the stimulation experiments carried out on rats, different respective predetermined stimulation parameters were employed, namely a respective stimulation frequency of 30 to 50 Hz, a stimulation pulse duration of 0.1 ms to 0.5 ms as well as a stimulation amplitude of 0.3 mA to 1.5 mA.
However, although the knowledge gained in the context of the previous animal experiments regarding manipulating the blood pressure by selective electrical stimulation of baroreceptive nerve fibers appears to be highly promising, at least the quantitative relationships between the electrical stimulation event and the biological response in the form of a drop in blood pressure initiated on the basis of an organic regulation mechanism is still poorly understood. Particularly with larger animals than the rats used in animal experiments until now, or indeed in humans, far more regulatory stimulations have to be carried out beforehand in order to arrive at an outcome for organic regulation which is within a quantitatively determined range of tolerances.